Research News

Anthracycline is one of the most effective chemotherapy drugs against aggressive cancers, but it is also one of the most dangerous for our hearts, which limits how much a patient can safely receive. Cancer sciences have operated for decades under a prevailing theory of what anthracycline drugs do to heart cells: they turn a critical enzyme off. New research from the laboratories of Jianjun Zhao, MD, PhD, and Wai Hong Wilson Tang, MD, shows that the biological truth is the exact opposite: the drugs dial enzyme production up.  

The Cleveland Clinic Research team’s study, published in Cancer Research Communications, uses these insights to develop an injection that protects the heart in preclinical models.  

“Anthracycline-induced cardiomyopathy has always been one of the most feared complications of cancer treatment. This is especially true for survivors of childhood cancer as they grow into adults,” says Dr. Tang, who treats many of these cases. “That’s the paradox of anthracycline. Even with medical advances, cancer survivors are more at risk for another potentially fatal disease.” 

The paradox of anthracycline 

Anthracycline is a powerful chemotherapy drug that can treat and even cure many cancers. Anthracyclines cause highly unstable molecules called free radicals to accumulate in the heart, leading to potentially fatal heart damage. The prevailing theory was that anthracyclines completely block an enzyme called topoisomerase 2 beta (TOP2B) by forming a complex of bound anthracycline, TOP2B and heart DNA. This prevents heart cells from turning on mitochondrial genes and triggers cell death. 

“The current theory is based on preclinical studies where researchers would completely delete the TOP2B gene out of heart cells, and see that the cells could then survive anthracycline drug treatment in the lab,” Dr. Zhao says. “But that theory has one critical flaw: nobody’s ever actually looked at what’s actually happening to TOP2B expression levels in a failing human heart.” 

The research team compared 17 healthy hearts from organ donors to 17 unhealthy hearts from individuals who got transplants to treat their anthracycline-induced heart failure. They were shocked by what they saw. 

“We expected to see the transplant patients’ hearts have little to no TOP2B expression, because anthracycline should be blocking the protein. Instead, most of the transplanted hearts had significantly higher levels of TOP2B compared to healthy donors,” Dr. Zhao says. "Engineering increasing  human TOP2B levels in preclinical models caused similar damage to heart cells and heart failure.” 

Further investigation showed that when heart cells make too much TOP2B, the excess proteins bind to and interfere with other proteins such as SMAD1 in the cell that are meant to keep the heart healthy. 

Moving from mechanism to medicine 

For a potential solution to anthracycline drugs’ toxicity, the team needed to find a way to keep TOP2B levels in a specific range. 

They developed an injectable drug that binds excess RNA from the TOP2B gene and prevents it from being made into protein. Testing the drug with anthracycline in preclinical models improved survival and heart function by over 75%.  

Drs. Zhao and Tang caution that the current iteration of their drug is meant to be a proof-of-concept. They are now working to further refine the targeted therapy and expand testing in additional models, with the end goal of developing a safe and effective injection cancer patients can take to protect their hearts during intensive chemotherapy. 

“[Co-corresponding author Jianhong Lin, MD, PhD] and I came here to do research after seeing the toll chemotherapy side effects took on our patients and knowing how little we could offer them in return,” says Dr. Zhao, who was a practicing physician before pivoting to the lab. “There’s a lot of work to do, but it’s exciting to finally understand the problem clearly and move toward solutions.”